Treatment of inflammatory, cancer, and thrombosis disorders

ABSTRACT

This invention provides for the treatment of inflammatory, cancer and thrombotic disorders through the administration, in combination, of a COX2 inhibitor, low dose aspirin, and antioxidant flavanoids, flavonoids or isoflavones and at least one of these combinations will be given in a subtherapeutic amount for improved anti-inflammatory, anti-cancer, and anti-thrombotic efficacy and safety.

FIELD OF THE INVENTION

This invention relates to the combination of enteric-coated low doseaspirin, antioxidants (falvanoids or flavonoids), and COX2 inhibitorsfor inflammatory, cancer and thrombosis disorders.

BACKGROUND OF THE INVENTION

One of the most adverse effects of nonsteroidal anti-inflammatory drugs(NSAIDs) is their ulcerogenic activity on the gastrointestinal tract.Flavonoids are shown to possess anti-inflammatory efficacy without theulcerogenic side effects (Parmar N S, Ghosh M N. In Proceedings of the6^(th) Hungarian Bioflavonoids Symposium. Farkas L., et al. (Ed.),Elsevier, Amsterdam 513-516, 1981). Examples of those flavanoids andflavonoids are as listed in the recent review (Lin J-K, Tsai S-H,Lin-Shiau S-Y. Drugs of the Future 26: 145-152; 2001). Flavanoids,flavonoids, and isoflavones are shown to be effective inhibitors ofangiogenesis, tumor growth and tumor metastasis (Igura K, Ohta T, KurodaY, Kaji K. cancer Lett. 171:11-16; 2001; Kimura Y, Okuda H. J Nutr. 131:1844-1849; 2001; Lin J-K, Tsai S-H, Lin-Shiau S-Y. Drugs of the Future26: 145-152; 2001). The recent marketing of two selective cyclooxygenase2 (COX-2) inhibitors climaxes the first phase of an exciting andfast-paced effort to exploit a novel molecular target for nonsteroidalanti-inflammatory drugs (NSAIDs). Much has been written in the lay andscientific press about the potential of COX-2 inhibitors asanti-inflammatory and analgesic agents that lack the gastrointestinalside-effects of traditional NSAIDs. Although research on COX-2inhibitors has focussed mainly on inflammation and pain, experimentaland epidemiological data suggest that COX-2 inhibitors could be used inthe treatment or prevention of a broader range of diseases. Recentreports suggested increased thrombogenicity of COX2-specific inhibitors(Catella-Lawson F, Crofford L J, Am J Med 110: p28S-32S; 2001) in highrisk patients suggesting the need for an adjunct antiplatelet agent.

Antiplatelet therapy has become a standard treatment of acute andchronic arterial thrombotic diseases. Among current availableanti-platelet drugs, aspirin is the drug of choice for secondaryprevention of myocardial infarction (Schror K. Antiplatelet drugs. Drugs50:7-28, 1995). Its antiplatelet activity is mainly due to theirreversible inhibition of the platelet cyclo-oxygenase causing alast-lasting blockade of platelet-dependent thromboxane A₂ formation.Since pro-inflammatory stimuli might trigger the extension ofthromboembolic disorders and vice versa, the combination of standarddose of COX2 inhibitors (anti-inflammatory) and aspirin(antiplatelet+limited anti-inflammatory) at the 70-85 mg would improvethe efficacy and safety of each other. Additionally, COX2 inhibitorssimilar to the flavanoids exhibited anti-angiogenesis and anti-tumorefficacy. Recent studies demonstrated overexpression of COX-2 inmultiple human tumors and pharmacological evidence in animal models,which indicate that COX-2 inhibitors could be used in the prevention ortreatment of a broader range of disease (Kalgutkar A S, Zhao Z. CurrDrug Targets. 2(1): 79-106, 2001).

Compared with traditional non-steroidal anti-inflammatory drug agents,use of COX-2 selective inhibitors is associated with decreased incidenceof adverse gastric events as a result of minimal inhibition ofgastroprotective COX-1, but with equivalent anti-inflammatory benefitthrough inhibition of COX-2 . However, there is evidence to suggest thatthe ‘COX-1=constitutive, COX-2=inflammatory’ paradigm is less distinctthan originally proposed. Furthermore, selective COX-2 inhibitors mayhave other consequences as a result of the change in the eicosanoidprofile. Thus, despite the relatively safe gastrointestinal profile,vigilant post-marketing surveillance for other adverse effects isrequired (Penglis P S, James M J, Cleland L G., Intern Med J2001;31(1):37-41). In that regard, recent clinical reports suggestedincreased thrombotic events in patients taking COX2 inhibitorssuggesting the urgent need for the use of the COX1 inhibitory efficacyof aspirin to improve such serious adverse outcome when using COX2inhibitors for long term.

The recent marketing of two selective cyclooxygenase-2 (COX-2 )inhibitors, celecoxib and rofecoxib is remarkable considering that COX-2was only discovered eight years ago as a growth factor- andcytokine-inducible gene. Concomitant with these pharmaceutical successesis the advances in our understanding of the molecular and structuralbasis for selective COX2 inhibition. In addition to the existinginhibitor classes, there are many novel structural classes which haverecently emerged due to a better understanding of the active sitedifferences between the two isozymes (Kalgutkar A S, Zhao Z., Curr DrugTargets 2001; 2(1): 79-106). In addition to its role in inflammation,recent studies suggest that COX-2 -derived prostaglandin may play apivotal part in the maintenance of tumor viability, growth, andmetastasis. NSAID epidemiological evidence, studies demonstratingoverexpression of COX-2 in multiple human tumors and pharmacologicalevidence in animal models, which indicate that COX-2 inhibitors could beused for the prevention or treatment of a broader range of disease.

SUMMARY OF THE INVENTION

One object of the present invention is to provide a method of preventingthrombotic complications due the long-term use of COX2 inhibitors and toenhance its anti-inflammatory and anticancer efficacy by combining itwith low dose enteric coated aspirin and flavanoids. This combinationtherapy in a mammal comprising: administering to said mammal thecombination in a therapeutically effective amount of (i) a COX2inhibitors selected from the group consisting of celecoxib(Celebrex^(R)), rofecoxib (Vioxx^(R)), and other specific COX2inhibitors (ii) aspirin and (iii) antioxidants selected from the groupconsisting of flavanoids, flavonoids or isoflavones, wherein at leastone of the COX2 inhibitors, at least one of the flavanoids and aspirinare used.

Another object of the present invention is to provide a method oftreating inflammatory disorders, cancer and thrombosis in a mammalwherein the combination of (i) and (ii) or (iii) above are administeredin amounts to provide a synergistic effect in improving the efficacy andsafety.

DETAILED DESCRIPTION OF THE INVENTION

The combinations of a COX2 inhibitors with aspirin and antioxidantsuseful in the treatment of inflammatory and thrombotic disordersincluding rheumatoid arthritis, atherosclerotic arterial disease,valvular heart disease, cerebrovascular disease such as stroke, atrialfibrillation, coronary artery disease such as myocardial infarction andunstable angina, coronary artery bypass grafts, peripheral vasculardisease, thromboembolic complications of prosthetic cardiovasculardevices such heart valves and vascular grafts. These combinations arealso expected to be useful in combining with endovascular stentingprocedures such as percutaneous transluminal coronary angioplasty, toprevent subsequent arterial thrombus formation and reocclusion. Alsouseful in the treatment of thrombosis is the combination in atherapeutically effective amount of tissue plasminogen activator and theGPIIb/IIIa antagonists. Specific examples of useful GPIIb/IIIaantagonist compounds are abciximab, eptifibatide, tirofiban, lamifiban,lefradafiban, sibrafiban (Ro-48-3657), orbofiban and xemilofibandescribed in the paper of Graul et al. and Scarborough (Graul A, MartelA M and Castaner J. Xemilifiban; Drugs of the Future 22: 508-517, 1997;Scarborough R M; Eptifibatide. Drugs of the Future 23: 585-590, 1998).Of these, lamifiban, lefradafiban, sibrafiban, orbofiban and xemilofibanare preferred. Others will be readily apparent to those skilled in theart.

“Therapeutically effective amount” is intended to include an amount of acombination of compounds claimed effective to treat inflammatory andthrombotic disorders in a mammal.

By “administered in combination”, “combination”, or “combined” whenreferring to compounds described herein, it is meant that the compoundsor components are administered concurrently to the mammal being treated.When administered in combination each compound or component or componentmay be administered at the same time or sequentially in any order or atdifferent points in time, so as to provide the desired therapeuticeffect.

DOSAGE AND FORMULATION

Combinations of standard doses of COX2 inhibitors, aspirin at dosesranging from 70-350 mg, and antioxidants are administered as treatmentfor inflammatory, cancer, and thrombotic disorders. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents.

Dosage forms of compositions suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose. starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

In general, water, suitable oil, saline, aqueous dextrose (glucose), andrelated sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and itssalts, and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-parabenand chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, a standard reference text in this field, the contentsof which are incorporated herein by reference.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 0.1 to 100 mg of powderedactive ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mgmagnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in digestible oil such as soybean oil,cottonseed oil or olive oil can be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 0.1 to 100 mg of the active ingredient. The capsules shouldthen be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures sothat the dosage unit is 0.1 to 100 mg of active ingredient, 0.2 mg ofcolloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.Appropriate coatings may be applied to increase palatability or delayabsorption.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 ml contain 0.1 to 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

The combined compounds of this invention may be formulated such that,although the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized. Inorder to minimize contact, for example, where the product is orallyadministered, one active ingredient may be enteric coated. By entericcoating one of the active ingredients, it is possible not only tominimize the contact between the combined active ingredients, but also,it is possible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for combined compounds wherein one of the active ingredients iscoated with a sustained-release material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation ofcombined compounds in which the one compound is coated with a sustainedand/or enteric release polymer, and the other compound is also coatedwith a polymer such as a low viscosity grade of hydroxypropylmethylcellulose or other appropriate materials as known in the art, inorder to further separate the active components. The polymer coatingserves to form an additional barrier to interaction with the othercomponent.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric-coated compound and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the combinedcompounds, whether administered in a single dosage form or administeredin separate forms but at the same time or concurrently by the samemanner, will be readily apparent to those skilled in the art, based onthe present disclosure.

Combination

Each therapeutic compound of this invention can independently be in anydosage form, such as those described above, and can also be administeredin various ways, as described above. For example, the compounds may beformulated together, in a single dosage unit (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.) as a combinationproduct. Alternatively, when not formulated together in a single dosageunit, an individual COX2 inhibitors may be administered at the same timeas either aspirin or antioxidants (flavanoids, flavonoids orisoflavones) or sequentially, in any order thereof.

As is appreciated by a medical practitioner skilled in the art, thedosage of the combination therapy of the invention may vary dependingupon various factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above.

The proper dosage of a COX2 inhibitor and low dose aspirin (35-150 mg)combination in an enteric coated formulation is the preferred form. Byway of general guidance, typically a daily dosage may be about 0.01milligram to about 1 gram of each component. By way of general guidance,when the compounds are administered in combination, the dosage amount ofeach component may be reduced by about 70-80% relative to the usualdosage of the component when it is administered alone as a single agentfor the treatment of thrombosis, in view of the synergistic effect ofthe combination.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1. A method of treating inflammation in a mammal, said method consistingessentially of concurrently administering to said mammal a therapeuticcomposition, said therapeutic composition comprising: (i) a standardtherapeutic dose of a COX2 inhibitor selected from the group consistingof celecoxib and rofecoxib; (ii) low dose aspirin in an amount of 70-85mg; and (iii) an antioxidant selected from the group consisting of aflavanoid, a flavonoid, an isoflavone, and combinations thereof.
 2. Themethod of claim 1, wherein the antioxidant is the flavanoid.
 3. Themethod of claim 1, wherein the antioxidant is the flavonoid.
 4. Themethod of claim 1, wherein the antioxidant is the isoflavone.
 5. Apharmaceutical composition, comprising a therapeutic composition fortreating inflammatory disorders in a mammal, said therapeuticcomposition comprising: (i) a standard therapeutic dose of a COX2inhibitor selected from the group consisting of celecoxib and rofecoxib;(ii) low dose aspirin in an amount of 70-85 mg; and (iii) an antioxidantselected from the group consisting of a flavanoid, a flavonoid, anisoflavone, and combinations thereof.
 6. The pharmaceutical compositionof claim 5, wherein the antioxidant is the flavanoid.
 7. Thepharmaceutical composition of claim 5, wherein the antioxidant is theflavonoid.
 8. The pharmaceutical composition of claim 5, wherein theantioxidant is the isoflavone.